The present invention is concerned with novel compounds of formula (I) having superior gastrokinetic properties. The invention further relates to methods for preparing such novel compounds, pharmaceutical compositions comprising said novel compounds as well as the use as a medicine of said compounds.
Journal of Medicinal Chemistry, 1993, 36, pp 4121-4123 discloses 4-amino-N-[(1-butyl-4-piperidinyl)methyl]-5-chloro-2-methoxy-benzamide as a potent and selective 5HT4-receptor antagonist.
WO 93/05038, published on Mar. 18, 1993 (SmithKline Beecham PLC) discloses a number of substituted 4-piperidinylmethyl 8-amino-7-chloro-1,4-benzodioxan-5-carboxamides having 5HT4-receptor antagonistic activity.
WO 94/10174, published on May 11, 1994 (SmithKline Beecham PLC) discloses a number of substituted 4-pyridinylmethyl oxazino[3,2-a]indole-carboxamide derivatives having 5HT4-receptor antagonistic activity.
The above prior art documents all disclose substituted 4-piperidinylmethyl carboxamides and the analogues thereof having 5HT4-receptor antagonistic activity. Compounds showing 5HT4 antagonism are taught to have potential interest in the treatment of, for example, irritable bowel syndrome, in particular the diarrhoea aspects of irritable bowel syndrome, i.e. these compounds block the ability of 5HT (which stands for 5-hydroxy-tryptamine, i.e. serotonin) to stimulate gut motility (see WO-93/05038, page 8, lines 12 to 17). The present gastroprokinetic compounds differ in structure mainly by the presence of a hydroxy- or an alkyloxy group on the central piperidine ring.
WO 93/16072, published on Aug. 19, 1993 discloses 5-amino-N-[(1-butyl-4-piperidinyl)methyl]-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide having 5 HT4 receptor antagonistic activity.
Bioorganic and Medicinal Chem. Lett., 1996, 6, pp. 263-266, and WO-96/33186 (Pharmacia S.P.A.), published on Oct. 24, 1996, disclose 4-amino-N-(1-butyl-4-piperidinyl)methyl-5-chloro-2,3-dihydro-7-benzoturancarboxamide having 5 HT4 receptor agonistic activity.
The compounds of the present invention differ from the previous prior art documents due to the presence of a hydroxy or a C1-6alkyloxy group on the 3 position of the central piperidine ring.
EP-0,299,566, published on Jan. 19, 1989, discloses N-(3-hydroxy-4-piperidinyl)benzamides having gastrointestinal motility stimulating activity.
EP-0,309,043, published on Mar. 29, 1989, discloses substituted N-(1-alkyl-3-hydroxy-4-piperidinyl)benzamides having gastrointestinal motility stimulating activity.
EP-0,389,037, published on Sep. 26, 1990, discloses N-(3-hydroxy-4-piperidinyl)(dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzodioxin)-carboxamide derivatives having gastrointestinal motility stimulating activity.
The latter three prior art documents all disclose carboxamide derivatives wherein the amide function is bonded directly with the piperidine ring, while the compounds of the present invention all have an amide function wherein a methylene group is present between the carbamoyl nitrogen and the piperidine ring.
EP-0,774,460, published on May 21, 1997, and WO-97/11054, published on Mar. 27, 1997 disclose a number of benzoic acid compounds as 5-HT4 agonists useful for treating gastric motility disorders.
The compounds of the present invention differ from the latter two prior art documents due to the presence of a hydroxy or a C1-6alkyloxy group on the 3- or 4-position of the central piperidine ring. Furthermore, those compounds of the present invention wherein R2 is other than hydrogen are also structurally different over said prior art documents.
The problem this invention sets out to solve is to provide compounds having gastrointestinal motility stimulating properties, particularly having superior gastric emptying activity. Preferably said compounds should be orally active.
The solution to this problem is provided by the novel compounds of formula (I) that differ structurally from the prior art, inter alia, by the presence of a hydroxy or a C1-6alkyloxygroup on the 3- or 4-position of the central piperidine ring, or by the presence of a methylene group between the carbamoyl group and the piperidine ring.
The present invention concerns a compound of formula (I) 
a stereochemically isomeric form thereof, an N-oxide form thereof or a pharmaceutically acceptable acid or base addition salt thereof,
wherein
R1 and R2 taken together form a bivalent radical of formula
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 (a-1),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94 (a-2),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94 (a-3),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 (a-4),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94 (a-5),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 (a-6),
wherein in said bivalent radicals one or two hydrogen atoms may be substituted with C1-6alkyl,
R3 is hydrogen or halo;
R4 is hydrogen or C1-6alkyl;
R5 is hydrogen or C1-6alkyl;
L is C3-6cycloalkyl, C5-6cycloalkanone, or C2-6alkenyl, or L is a radical of formula
xe2x80x94Alkxe2x80x94R6 (b-1),
xe2x80x94Alkxe2x80x94Xxe2x80x94R7 (b-2),
xe2x80x94Alkxe2x80x94Yxe2x80x94C(xe2x95x90O)xe2x80x94R9 (b-3), or
xe2x80x94Alkxe2x80x94Yxe2x80x94C(xe2x95x90O)xe2x80x94NR11R12 (b-4),
wherein each Alk is C1-12alkanediyl; and
R6 is hydrogen, hydroxy, cyano, C1-6alkylsulfonylamino, C3-6cycloalkyl, C5-6cycloalkanone, or Het1;
R7 is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C3-6cycloalkyl, or Het2;
X is O, S, SO2 or NR8; said R8 being hydrogen or C1-6alkyl;
R9 is hydrogen, C1-6alkyl, C3-6cycloalkyl, C1-6alkyloxy or hydroxy;
Y is NR10 or a direct bond, said R10 being hydrogen or C1-6alkyl;
R11 and R12 each independently are hydrogen, C1-6alkyl, C3-6cycloalkyl, or R11 and R12combined with the nitrogen atom bearing R11 and R12 may form a pyrrolidinyl or piperidinyl ring both being optionally substituted with C1-6alkyl, amino or mono or di(C1-6alkyl)amino, or said R11 and R12 combined with the nitrogen bearing R11 and R12 may form a piperazinyl or 4-morpholinyl radical both being optionally substituted with C1-6alkyl; and
Het1 and Het2 each independently are selected from furan: furan substituted with C1-6alkyl or halo; tetrahydrofuran; a tetrahydrofuran substituted with C1-6alkyl; a dioxolane; a dioxolane substituted with C1-6alkyl, a dioxane; a dioxane substituted with C1-6alkyl; tetrahydropyran; a tetrahydropyran substituted with C1-6alkyl; pyrrolidinyl; pyrrolidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, or C1-6alkyl; pyridinyl; pyridinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyl; pyrimidinyl; pyrimidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyl, C1-6alkyloxy, amino and mono and di(C1-6alkyl)amino; pyridazinyl; pyridazinyl substituted with one or two substituents each independently selected from hydroxy, C1-6alkyloxy, C1-6alkyl or halo; pyrazinyl; pyrazinyl substituted with one ore two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyl, C1-6alkyloxy, amino, mono- and di(C1-6alkyl)amino and C1-6alkyloxycarbonyl;
Het1 can also be a radical of formula 
Het1 and Het2 each independently can also be selected from the radicals of formula 
R13 and R14 each independently are hydrogen or C1-4alkyl.
As used in the foregoing definitions halo is generic to fluoro, chloro, bromo and iodo; C1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methyl-ethyl, 2-methylpropyl and the like; C1-6alkyl is meant to include C1-4alkyl and the higher homologues thereof having 5 or 6 carbon atoms, such as, for example, 2-methyl-butyl, pentyl, hexyl and the like; C3-6cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C2-6alkenyl defines straight and branched chain unsaturated hydrocarbon radicals having from 2 to 6 carbon atoms, such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; C1-12alkanediyl defines bivalent straight or branched chain hydrocarbon radicals containing from 1 to 12 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl, 1,11-undecanediyl, 1,12-dodecanediyl and the branched isomers thereof. C1-6alkanediyl is defined in an analogous way as C1-12alkanediyl.
The xe2x80x94OR4 radical is preferably situated at the 3- or 4-position of the piperidine moiety.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.
The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids: or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butane-dioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.
The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. For instance, when an aromatic heterocyclic ring is substituted with hydroxy the keto-form may be the mainly populated tautomer.
The N-oxide forms of the compounds of formula (I), which may be prepared in art-known manners, are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the N-oxide. Particularly those N-oxides are envisaged wherein the piperidine-nitrogen is N-oxidized.
A group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply:
a) R1 and R2 taken together form a radical of formula (a-1), (a-2), (a-3), (a-4), (a-5) or (a-6), wherein optionally one or two hydrogen atoms are substituted with C1-4alkyl;
b) R3 is fluoro, chloro or bromo; in particular chloro;
c) R4 is hydrogen or methyl, and the xe2x80x94OR4 radical is situated at the 3- or 4-position of the piperidine ring; or
d) R5 is hydrogen.
More interesting compounds are those compounds of formula (I) wherein R1 and R2 taken together form a radical of formula (a-2), or (a-4), wherein optionally one or two hydrogen atoms are substituted with methyl.
Further more interesting compounds are those interesting compounds of formula (I) wherein R4 is hydrogen or methyl.
Particular compounds are those more interesting compounds wherein the xe2x80x94OR4 radical is situated at the 3-position of the central piperidine moiety having the trans configuration, i.e. the xe2x80x94OR4 radical is in the trans position in relation to the methylene on the central piperidine moiety.
Other particular compounds are those more interesting compounds wherein the xe2x80x94OR4 radical is situated at the 4-position of the central piperidine moiety.
Very particular compounds are those compounds wherein L is:
C3-6cycloalkyl or C2-6alkenyl; or
a radical of formula (b-1), wherein each Alk is C1-6alkanediyl, and R6 is hydrogen, hydroxy, cyano, amino, C1-6alkylsulfonylamino, C3-6cycloalkyl or Het1, wherein Het1 is tetrahydrofuran; dioxolane; dioxolane substituted with C1-6alkyl; tetrahydropyran; pyridazinyl substituted with one or more substituents selected from hydroxy, halo and C1-6alkyl; or a radical of formula (c-1), (c-3) or (c-4) wherein R13 is C1-4alkyl; or
a radical of formula (b-2), wherein Alk is C1-6alkanediyl, X is O, and R7 is C1-6alkyl or hydroxyC1-6alkyl; or
a radical of formula (b-2), wherein Alk is C1-6alkanediyl, R7 is Het2 wherein Het2 is pyrazinyl substituted with C1-6alkyl, and X is NR8 wherein R8 is hydrogen or C1-6alkyl; or
a radical of formula (b-3) wherein Y is a direct bond, and R9 is C1-6alkyl, hydroxy or C1-6alkyloxy; or
a radical of formula (b-4) wherein Y is a direct bond, and R11 and R12 are C1-6alkyl, or
R11 and R12 combined with the nitrogen atom bearing R11 and R12 form pyrrolidinyl.
Preferred compounds are those compounds wherein L is butyl; propyl substituted with methoxy, methylcarbonyl or 2-methyl-1,3-dioxolane; ethyl substituted with 4-methyl-2-pyridazinone or tetrahydropyranyl; or methyl substituted with tetrahydrofuranyl or tetrahydropyranyl.
Most preferred are:
trans-4-amino-N-[(1-butyl-3-hydroxy-4-piperidinyl)methyl]-5-chloro-2,3-dihydro-7-benzofurancarboxamide,
trans-4-amino-5-chloro-2,3-dihydro-N-[[3-hydroxy-1-(3-methoxypropyl)-4-piperidinyl]methyl]-7-benzofurancarboxamide,
trans-4-amino-5-chloro-2,3-dihydro-N-[3-hydroxy-1-[(tetrahydro-2-furanyl)methyl]-4-piperidinyl]-7-benzofurancarboxamide,
trans-4-amino-5-chloro-2,3-dihydro-N-[[3-hydroxy-1-(4-oxopentyl)-4-piperidinyl]methyl]-7-benzofurancarboxamide,
trans-4-amino-5-chloro-2,3-dihydro-N-[3-hydroxy-1-[(tetrahydro-2-pyranyl)methyl]-4-piperidinyl]-7-benzofurancarboxamide,
trans-4-amino-5-chloro-2,3-dihydro-N-[[3-methoxy-1-(3-methoxypropyl)-4-piperidinyl]methyl]-7-benzofurancarboxamide,
trans-4-amino-5-chloro-2,3-dihydro-N-[[3-methoxy-1-[(tetrahydro-2-furanyl)methyl]-4-piperidinyl]methyl]-7-benzofurancarboxamide,
trans-4-amino-5-chloro-2,3-dihydro-N-[[3-hydroxy-1-(3-methoxypropyl)-4-piperidinyl]methyl]-2,2-dimethyl-7-benzofurancarboxamide,
trans-4-amino-5-chloro-2,3-dihydro-N-[[3-methoxy-1-(4-oxopentyl)-4-piperidinyl]methyl]-7-benzofurancarboxamide,
trans-5-amino-N-[(1-butyl-3-hydroxy-4-piperidinyl)methyl]-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide, and the stereoisomeric forms, the pharmaceutically acceptable acid or base addition salts, or the N-oxides thereof; and
trans-(xe2x88x92)-4-amino-5-chloro-2,3-dihydro-N-[[3-hydroxy-1-(3-methoxypropyl)-4-piperidinyl]methyl]-2,2-dimethyl-7-benzofurancarboxamide, a pharmaceutically acceptable acid addition salt or an N-oxide form thereof.
The compounds of the present invention can generally be prepared by N-alkylating an intermediate of formula (III) with an intermediate of formula (II), wherein W is an appropriate leaving group such as, for example, halo, e.g. fluoro, chloro, bromo, iodo, or in some instances W may also be a sulfonyloxy group, e.g. methanesulfonyloxy, benzenesulfonyloxy, trifluoromethanesulfonyloxy and the like reactive leaving groups. The reaction can be performed in a reaction-inert solvent such as, for example, acetonitrile, and optionally in the presence of a suitable base such as, for example, sodium carbonate, potassium carbonate or triethylamine. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and the reflux temperature of the reaction mixture. 
Alternatively, compounds of formula (I) can also be prepared by reductively N-alkylating an intermediate of formula (III) with an intermediate of formula Lxe2x80x2xe2x95x90O (IV), wherein Lxe2x80x2xe2x95x90O represents a derivative of formula Lxe2x80x94H wherein two geminal hydrogen atoms are replaced by oxygen, following art-known reductive N-alkylation procedures. 
Said reductive N-alkylation can be performed in a reaction-inert solvent such as, for example, dichloromethane, ethanol, toluene or a mixture thereof, and in the presence of a reducing agent such as, for example, a borohydride, e.g. sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride. It may also be convenient to use hydrogen as a reducing agent in combination with a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal. In case hydrogen is used as reducing agent, it may be advantageous to add a dehydrating agent to the reaction mixture such as, for example, aluminium tert-butoxide. In order to prevent the undesired further hydrogenation of certain functional groups in the reactants and the reaction products, it may also be advantageous to add an appropriate catalyst-poison to the reaction mixture, e.g., thiophene or quinoline-sulphur. To enhance the rate of the reaction, the temperature may be elevated in a range between room temperature and the reflux temperature of the reaction mixture and optionally the pressure of the hydrogen gas may be raised.
The compounds of formula (I) may be prepared by reacting an intermediate of formula (V) with an carboxylic acid derivative of formula (VI) or a reactive functional derivative thereof, such as for example carbonyl imidazole derivatives. Said amide-bond formation may be performed by stirring the reactants in an appropriate solvent, optionally in the presence of a base, such as sodium imidazolide. 
Further, compounds of formula (I) can be prepared by carbonylation of an intermediate of formula (VII), wherein X is bromo or iodo, in the presence of an intermediate of formula (V). 
Said carbonylation reaction can be carried out in a reaction-inert solvent such as, e.g. acetonitrile or tetrahydrofuran, in the presence of a suitable catalyst and a suitable base such as a tertiary amine e.g. triethylamine, and at a temperature ranging between room temperature and the reflux temperature of the reaction mixture. Suitable catalysts are, for instance, palladium(triphenylphosphine) complexes. Carbon monoxide is administered at atmospheric pressure or at an increased pressure. Analogous carbonylation reactions are described in Chapter 8 of xe2x80x9cPalladium reagents in organic synthesesxe2x80x9d, Academic Press Ltd., Benchtop Edition 1990, by Richard F. Heck; and the references cited therein.
Said amide formation reaction is known from the above mentioned reference with metal catalysts which are soluble such as palladium (triphenylphosphine) complexes. Unexpectedly, we deem to have found that these reactions can also be performed on metal catalysts which are insoluble or immobilized on a solid carrier. Suitable catalysts are for example palladium-on-carbon. Raney nickel or Cu2O. These insoluble catalysts or catalysts on a solid phase are much less expensive than the metal complexes and are often much easier to handle when synthesis is done on an industrial scale.
In other words, we have found a novel and inventive way to prepare amides in the following way: 
In the above formulas Rd represent any substituent possible on a phenyl, n is an integer from 1 to 5, and Rxe2x80x2Rxe2x80x3NH can be any primary or secundary amine. The term halide suitably refers to chloro, bromo, iodo. Preferred halides are bromo and iodo.
The preferred catalyst is palladium-on-carbon.
The pressure of CO, i.e. carbon monoxide, may vary according to the substrates and reactants and a person skilled in the art will certainly be able to find a suitable range after little straightforward experimentation. The preferred pressure of CO, i.e. carbon monoxide, is 50 kg/cm2 (about 4.9xc3x97106 Pa). It may suitably range between about 1 kg/cm2 (about 1xc3x97105 Pa) and about 100 kg/cm2 (about 10xc3x97106 Pa).
The reaction temperature may range from room temperature to the reflux temperature of the reaction mixture.
This reaction is preferably performed in a solvent, which can be in the amine Rxe2x80x2Rxe2x80x3NH itself, or in acetonitrile or in tetrahydrofuran.
Preferably said Rxe2x80x2Rxe2x80x3NH amine is a primary amine.
Suitably a base is also present. An interesting suitable base is for instance triethylamine.
The starting materials and some of the intermediates are known compounds and are commercially available or may be prepared according to conventional reaction procedures generally known in the art. For example, a number of intermediates of formula (VI) may be prepared according to art-known methodologies described in EP-0,389,037.
However, some intermediates of formula (VI) are novel and, hence, the invention also provides novel intermediates of formula (VI) wherein R1 is methoxy, R2 is methyl or methoxy and R3 is chloro. Said novel intermediates of formula (VI) are prepared as described in Example A.3.
An intermediate of formula (III) may be prepared by reacting an intermediate of formula (VIII), wherein PG represents an appropriate protective group, such as for example a tert-butoxycarbonyl or a benzyl group or a photoremovable group, with an acid of formula (VI), or an appropriate reactive functional derivative thereof, such as for example carbonyl imidazole derivatives, and subsequent deprotection of the thus formed intermediate, i.e. removal of PG by art-known methods. 
An intermediate of formula (V) may be prepared by reacting an intermediate of formula (X), with an intermediate of formula (II). Said intermediate of formula (X) may be prepared by deprotection of an intermediate of formula (VIII). 
In some cases, it may be appropriate to protect the amine functionality bearing the R5 radical in the above described reaction sequence. Protecting groups for amine functionalities are art-known. These protecting groups may then be removed at the appropriate time during the further synthesis.
Intermediates of formula (VIII-a), being intermediates of formula (VIII) wherein PG1 is a protecting group which cannot be removed by hydrogenation such as e.g. a tert-butoxycarbonyl, can be prepared according to scheme 1.
In scheme 1, an intermediate of formula (XI-a) is converted to an intermediate of formula (XII), wherein W1 is a leaving group such as halo or sulfonyloxy. Subsequently, intermediate (XII) is treated with an intermediate of formula (XIII), wherein PG2 is a protecting group which can be removed by hydrogenation such as, e.g. benzyl. Removal of the protecting group PG2 from intermediate (XIV) yields intermediates of formula (VIII-a).
Intermediates of formula (VII-a-1), defined as intermediates of formula (VIII-a) wherein R4 is methyl, can be prepared as described in scheme 2.
In scheme 2, an intermediate of formula (XI-a), wherein R4a is hydrogen, is converted to an intermediate of formula (XII-1), wherein W2 is a suitable leaving group such as e.g. a tosylate group. Subsequently, the secundary hydroxy of intermediate (XII-1), i.e. the xe2x80x94OR4a moiety, is converted to a methoxy using suitable methylation conditions such as e.g. treatment with sodium hydride in tetrahydrofuran and addition of methyliodide. Conversion of intermediate (XX) to intermediate (VII-a-1) can be done using art-known reaction procedures.
In an aspect of the present invention, novel compounds of formula (IX) are provided wherein R15 and R16 are each independently selected from hydrogen or a protective group PG, and R4 and R5 are as defined above. Suitable protecting groups PG are, e.g. C1-4alkylcarbonyl, C1-4alkyloxycarbonyl, trihalomethylcarbonyl, diphenylmethyl, triphenylmethyl or arylmethyl, wherein aryl is phenyl optionally substituted with up to two substituents selected from C1-4alkyloxy or halo. Said novel compounds of formula (IX) comprise the intermediates of formula (VIII), (X) and (XIV). 
Intermediates of formula (XI-a), wherein PG1 is a protecting group which cannot be removed by hydrogenation such as e.g. a tert-butoxycarbonyl, can be converted to intermediates of formula (XI-b), wherein PG2 is a protecting group which can be removed by hydrogenation such as, e.g. benzyl, using an appropriate deprotection-protection reaction sequence. Conversely, intermediates of formula (XI-b) can also be converted to intermediates of formula (XI-a). 
An intermediate of formula (XI-b), wherein the xe2x80x94OR4 moiety is located on the 3-position of the piperidine moiety, R4 is a hydrogen and PG2 is a benzyl group, having the trans configuration, is known from J. Med. Chem., 16, pp. 156-159 (1973). Said article also describes an intermediate of formula (XIX), wherein the xe2x80x94OR4 moiety is located on the 3-position of the piperidine moiety and R4 is a hydrogen, having the trans configuration.
Intermediates of formula (XI-1-a) are defined as intermediates of formula (XI-a) wherein the xe2x80x94OR4 moiety is located on the 3-position of the piperidine moiety. 
Those intermediates of formula (XI-1-a) wherein R4 is C1-6alkyl and having the cis configuration can be prepared by hydrogenating an intermediate of formula (XVI) following art-known methods. The intermediate (XVI), wherein PG1 and PG2 are as defined above, can be prepared by reacting a protected piperidone of formula (XV) with a phosphonium reagent of formula [(aryl)3Pxe2x80x94CH2xe2x80x94Oxe2x80x94PG2]+-halidexe2x88x92, in appropriate conditions for carrying out a Wittig-type reaction. Subsequent removal of PG2 yields intermediates of formula (XI-1-a) having the cis configuration. 
A novel way of preparing an intermediate of formula (XI-1-b) having the trans-configuration was found. Said novel preparation starts from an intermediate of formula (XI-1-b) having the cis-configuration or from an intermediate of formula (XVII) having the cis-configuration. In said intermediates of formula (XI-1-b) and (XVII) PG2 is as defined above, R4a is hydrogen, C1-6alkyl or a protective group such as for example, benzyl, tert-butoxycarbonyl and the like. 
Said inversion-reaction is carried out in an appropriate solvent, such as, for example an ether, e.g. tetrahydrofuran in the presence of CuO.Cr2O3 under a hydrogen atmosphere and in the presence of an appropriate base, such as, for example calciumoxide.
The preferred hydrogen pressure and reaction temperature is dependent upon the starting material. Starting from cis-(XI-1-b) the hydrogen pressure preferably ranges from 900 to 2000 kPa (measured at room temperature) and the reaction temperature ranges from room temperature up to 200xc2x0 C. preferably the reaction temperature is about 120xc2x0 C.
When starting from cis-(XVII), the preferred hydrogen pressure range is from 1500 kPa to 2200 kPa, preferably between 1800 kPa to 2000 kPa. The reaction temperature is between 100xc2x0 C. and 200xc2x0 C. preferably at about 125xc2x0 C. Apparently an equilibrium is reached, typically with a diastereomeric ratio of about 65:35 (trans:cis) as determined by gas chromatography. However via recrystallization it is possible to purify the desired trans-isomer. A suitable solvent for recrystallization is an ether, e.g. diisopropyl ether.
The pure intermediate of formula trans-(XI-1-b) having the trans configuration can also be obtained by chromatographic techniques, such as, for example gravitation chromatography or (H)PLC, starting from the cis/trans mixture of the intermediate (XI-1-b).
Still another novel way of preparing intermediates of formula trans-(XI-1-b) is to react an intermediate of formula (XVII) with borane or a borane derivative. Borane itself is commercially available as a borane-tetrahydrofuran complex. Borane derivatives, especially chiral borane derivatives are also commercially available. The reaction with borane is performed in a reaction inert solvent, preferable an ether, e.g. tetrahydrofuran. While adding the borane or the borane derivative the reaction mixture is kept at temperatures below 0xc2x0 C., interestingly at a temperature of about xe2x88x9230xc2x0 C. After adding the borane or the borane derivative to the reaction mixture the mixture is allowed to heat up while stirring is continued. The mixture is stirred for several hours. Subsequently, a hydroxide, e.g. sodium hydroxide is added as well as a peroxide, e.g. hydrogen peroxide and the reaction mixture is stirred at elevated temperatures for several hours. After this treatment the reaction product was isolated in art-known manner. 
Intermediates of formula (XVIII) can be prepared by reacting an intermediate of formula (XXI), wherein PG2 is as defined above and W is a leaving group as defined above, with an intermediate of formula (XXII), and subsequent reduction of the so-obtained intermediate (XXIII) with sodium borohydride, yielding intermediates of formula (XVIII). 
Said reaction procedure can also be used to prepare intermediates of formula (V). Consequently, an intermediate of formula (II) is reacted with an intermediate of formula (XXII) and the so-obtained intermediate of formula (XXIV) is reduced to an intermediate of formula (XXV) using sodium borohydride. Subsequently, the intermediates of formula (XXV) are converted to intermediates of formula (XXVI) using the above-described reaction procedure for the conversion of intermediates (XVIII) to intermediates of formula trans-(XI-b). 
Intermediates of formula (XXVI) can be converted to intermediates of formula (V) having the trans configuration, using a reaction procedure as describe above in Scheme 1 or Scheme 2.
Intermediates of formula (VIII-a) are defined as intermediates of formula (VIII) wherein the xe2x80x94OR4 moiety is located on the 4-position of the piperidine moiety and R4 is hydrogen. 
Said intermediates of formula (VIII-a) can be prepared by reacting an intermediate of formula (XXVII) with nitromethane under suitable reaction conditions, such as, e.g. sodium methoxide in methanol, and subsequently converting the nitro group into an amine group, thereby yielding the intermediates of formula (VIII-a). 
Intermediates of formula (V-a), defined as intermediates of formula (V) wherein R5 is hydrogen, can be prepared as following: 
An intermediate of formula (II) is reacted with an intermediate of formula (XXIX), wherein PG3 is a suitable protecting group such as xcfx81-toluenesulfonyl, and the so-obtained intermediate of formula (XXX) is reduced to an intermediate of formula (XXXI) using sodium borohydride. Subsequently, the intermediates of formula (XXXI) are converted to intermediates of formula (XXXII) using the above-described reaction procedure for the conversion of intermediates (XVIII) to intermediates of formula trans-(XI-b). Subsequently, removing the protecting group PG3 from intermediates (XXXII) yields the intermediates of formula (V-a).
The compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable salts and stereoisomeric forms thereof possess favourable intestinal motility stimulating properties. In particular the present compounds show significant gastric emptying activity as is evidenced in pharmacological example C-1, the xe2x80x9cGastric emptying of an acaloric liquid meal delayed by administration of lidamidine in conscious dogsxe2x80x9d-test.
The compounds of formula (I) also are shown to have a beneficial effect such as increase of basal pressure of the LES, i.e. Lower Esophageal Sphincter.
Most of the intermediates of formula (III) have shown to have analogous activity as the final compounds of formula (I).
In view of the capability of the compounds of the present invention to enhance the gastrointestinal motility, and in particular to activate gastric emptying, the subject compounds are useful to treat conditions related to a hampered or impaired gastric emptying and more generally to treat conditions related to a hampered or impaired gastrointestinal transit.
In view of the utility of the compounds of formula (I), it follows that the present invention also provides a method of treating warm-blooded animals, including humans, (generally called herein patients) suffering from conditions related to a hampered or impaired gastric emptying or more generally suffering from conditions related to a hampered or impaired gastrointestinal transit. Consequently a method of treatment is provided for relieving patients suffering from conditions, such as, for example, gastro-oesophageal reflux, dyspepsia, gastroparesis, constipation, post-operative ileus, and intestinal pseudo-obstruction. Gastroparesis can be brought about by an abnormality in the stomach or as a complication of diseases such as diabetes, progressive systemic sclerosis, anorexia nervosa and myotonic dystrophy. Constipation can result from conditions such as lack of intestinal muscle tone or intestinal spasticity. Post-operative ileus is an obstruction or a kinetic impairment in the intestine due to a disruption in muscle tone following surgery. Intestinal pseudo-obstruction is a condition characterized by constipation, colicky pain, and vomiting, but without evidence of physical obstruction. The compounds of the present invention can thus be used either to take away the actual cause of the condition or to relief the patients from symptoms of the conditions. Dyspepsia is an impairment of the function of digestion, that can arise as a symptom of a primary gastrointestinal dysfunction, especially a gastrointestinal dysfunction related to an increased muscle tone or as a complication due to other disorders such as appendicitis, galbladder disturbances, or malnutrition.
The symptoms of dyspepsia may also arise due to the intake of chemical substances, e.g. Selective Seretonine Re-uptake Inhibitors (SSRI""s), such as fluoxetine, paroxetine fluvoxamine, and sertraline.
Additionally some of the compounds also are stimulators of kinetic activity on the colon.
Hence, the use of a compound of formula (I) as a medicine is provided, and in particular the use of a compound of formula (I) for the manufacture of a medicine for treating conditions involving a decreased gastrointestinal motility, in particular decreased gastric emptying. Both prophylactic and therapeutic treatment are envisaged.
To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. Acid addition salts of (I) due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
For oral administration, the pharmaceutical compositions may take the form of solid dose forms, for example, tablets (both swallowable-only and chewable forms), capsules or gelcaps, prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art.
Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means, optionally with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methylcellulose, hydroxypropyl methylcellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).
Pharmaceutically acceptable sweeteners comprise preferably at least one intense sweetener such as saccharin, sodium or calcium saccharin, aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside or sucralose (4,1xe2x80x2,6xe2x80x2-trichloro-4,1xe2x80x2,6xe2x80x2-trideoxygalactosucrose), preferably saccharin, sodium or calcium saccharin, and optionally a bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey.
Intense sweeteners are conveniently employed in low concentrations. For example, in the case of sodium saccharin, the concentration may range from 0.04% to 0.1% (w/v) based on the total volume of the final formulation, and preferably is about 0.06% in the low-dosage formulations and about 0.08% in the high-dosage ones. The bulk sweetener can effectively be used in larger quantities ranging from about 10% to about 35%, preferably from about 10% to 15% (w/v).
The pharmaceutically acceptable flavours which can mask the bitter tasting ingredients in the low-dosage formulations are preferably fruit flavours such as cherry, raspberry, black currant or strawberry flavour. A combination of two flavours may yield very good results. In the high-dosage formulations stronger flavours may be required such as Caramel Chocolate flavour, Mint Cool flavour. Fantasy flavour and the like pharmaceutically acceptable strong flavours. Each flavour may be present in the final composition in a concentration ranging from 0.05% to 1% (w/v). Combinations of said strong flavours are advantageously used. Preferably a flavour is used that does not undergo any change or loss of taste and colour under the acidic conditions of the formulation.
The formulations of the present invention may optionally include an anti-flatulent, such as simethicone, alpha-D-galactosidase and the like.
The compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example as a sparingly soluble salt.
The compounds of the invention may be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multidose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as isotonizing, suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water before use.
The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration the compounds of the invention may be used, for example, as a liquid spray, as a powder or in the form of drops.
In general it is contemplated that a therapeutically effective amount would be from about 0.001 mg/kg to about 2 mg/kg body weight, preferably from about 0.02 mg/kg to about 0.5 mg/kg body weight. A method of treatment may also include administering the active ingredient on a regimen of between two or four intakes per day.
In the procedures described hereinafter the following abbreviations were used: xe2x80x9cACNxe2x80x9d stands for acetonitrile: xe2x80x9cTHFxe2x80x9d, which stands for tetrahydrofuran: xe2x80x9cDCMxe2x80x9d stands for dichloromethane; xe2x80x9cDIPExe2x80x9d stands for diisopropylether xe2x80x9cEtOAcxe2x80x9d stands for ethyl acetate; xe2x80x9cNH4OAcxe2x80x9d stands for ammonium acetate: xe2x80x9cHOAcxe2x80x9d stands for acetic acid; xe2x80x9cMIKxe2x80x9d stands for methyl isobutyl ketone.
For some chemicals the chemical formula was used, e.g. NaOH for sodium hydroxide, K2CO3 for potassium carbonate. H, for hydrogen gas, MgSO4 for magnesium sulfate, CuO.Cr2O3 for copper chromite. N2 for nitrogen gas, CH2Cl2 for dichloromethane, CH3OH for methanol, NH3 for ammonia. HCl for hydrochloric acid, NaH for sodium hydride, CaCO3 for calcium carbonate, CO for carbon monoxide, and KOH for potassium hydroxide.
Of some compounds of formula (I) the absolute stereochemical configuration was not experimentally determined. In those cases the stereochemically isomeric form which was first isolated is designated as xe2x80x9cAxe2x80x9d and the second as xe2x80x9cBxe2x80x9d, without further reference to the actual stereochemical configuration.
A. Preparation of the Intermediates